title: Q-site inhibitor induced ROS production of mitochondrial complex II is attenuated by TCA cycle dicarboxylates.
abstract: The impact of complex II (succinate:ubiquinone oxidoreductase) on the mitochondrial production of reactive oxygen species (ROS) has been underestimated for a long time. However, recent studies with intact mitochondria revealed that complex II can be a significant source of ROS. Using submitochondrial particles from bovine heart mitochondria as a system that allows the precise setting of substrate concentrations we could show that mammalian complex II produces ROS at subsaturating succinate concentrations in the presence of Q-site inhibitors like atpenin A5 or when a further downstream block of the respiratory chain occurred. Upon inhibition of the ubiquinone reductase activity, complex II produced about 75% hydrogen peroxide and 25% superoxide. ROS generation was attenuated by all dicarboxylates that are known to bind competitively to the substrate binding site of complex II, suggesting that the oxygen radicals are mainly generated by the unoccupied flavin site. Importantly, the ROS production induced by the Q-site inhibitor atpenin A5 was largely unaffected by the redox state of the Q pool and the activity of other respiratory chain complexes. Hence, complex II has to be considered as an independent source of mitochondrial ROS in physiology and pathophysiology.
authors.affiliation: Clinic of Anesthesiology, Intensive-Care Medicine and Pain Therapy, Goethe-University Hospital, Theodor-Stern Kai 7, Frankfurt am Main, Germany.
authors.forename: Ilka
authors.initials: I
authors.lastname: Siebels
authors.forename: Stefan
authors.initials: S
authors.lastname: Dröse
mesh_terms: D000818:Animals; D001665:Binding Sites; D002417:Cattle; D002952:Citric Acid Cycle / Q000187:drug effects*; D003998:Dicarboxylic Acids / Q000378:metabolism*; D004579:Electron Transport / Q000187:drug effects*; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors / Q000378:metabolism; D042963:Electron Transport Complex II / Q000187:drug effects / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000378:metabolism; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism*; D011728:Pyridones / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D019802:Succinic Acid / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D014451:Ubiquinone / Q000378:metabolism
chemical_list: D003998:Dicarboxylic Acids; D011728:Pyridones; D017382:Reactive Oxygen Species; D013481:Superoxides; C058278:atpenin A5; D014451:Ubiquinone; D019802:Succinic Acid; D006861:Hydrogen Peroxide; D042963:Electron Transport Complex II; D042967:Electron Transport Complex I
keywords: 2-n-decyl-quinazolin-4-yl-amine; 2-thenoyltrifluoroacetone; Atpenin A5; Complex II; DQA; Dicarboxylates; FAD; HRP; Mitochondria; NAD(+)/NADH; Q; Q(o) site; Q-site; QFR; RET; ROS; Reactive oxygen species (ROS); SMP; SOD; SQR; Succinate:ubiquinone oxidoreductase; TTFA; flavin adenine dinucleotide; horseradish peroxidase; oxidized/reduced from of nicotinamide adenine dinucleotide; quinol:fumarate oxidoreductases; reactive oxygen species; reverse electron transfer; submitochondrial particles; succinate:quinone oxidoreductases; superoxide dismutase; ubiquinol oxidation site of cytochrome bc(1) complex (complex III); ubiquinone; ubiquinone reduction site of complex II